Friday, April 29, 2011

Chemistry Pt. 2 - or - When good neurotransmitters go bad...

The diagram at right shows the general process of neuron-to-neuron signaling by neurotransmitters - chemical signaling agents produced by neurons, released by neurons, acting on neurons, and degraded by or in the vicinity of neurons. This general scheme is true for the "catecholamines" (norepinephrine, dopamine, serotonin) and GABA. Acetylcholine differs in that the molecule is first split into acetyl and choline halves before before taken up by the transmitting neuron.

The action of a neurotransmitter at a synapse is limited by (A) how much neurotransmitter reaches the receptors, (B) how quickly it is taken back up by the neurons, and (C) how quickly it is broken down. There are a number of ways to subvert this system - block the receptors, block the reuptake transporter, block the metabolic enzymes, etc. Many plant and animal toxins block the receptors. Insecticides and nerve agents block the metabolic enzymes, anesthetics block the receptors and/or the transporters, and chemicals similar in structure to neurotransmitters can mimic the normal chemical and interfere with any or all three processes.

This brings us to the subject of "Good Neurotransmitters Gone Bad..."

The chemical structures above show several of the neurotransmitters (circled) introduced in the previous blog, and the major psychoactive drugs that interfere with them. Note that each category of abused drugs correspond to one or more natural neurotransmitter drugs (except one, and we will get to that later). In each case, there is some similarity in chemical formula - or more importantly, 3-D chemical shape - between the abused drug and the neurotransmitter. This allows the abused drug to mimic the neurotransmitter at the receptor, or interfere with the reuptake transporters and/or metabolic enzymes (usually because they are not *guite* the same shape/formula) and thereby increasing the amount of time that the neurotransmitter is present in the synapse.

Note also that with the Narcotics, we introduce another neurotransmitter - enkephalin - which is present mostly in the spinal cord (but also in brain) to modulate the sensation of pain.

Then there's that lonely little THC molecule down in the lower left. Tetrahydrocannabinol is the main psychoactive ingredient in marijuana. For years it was thought to act either at the same receptors as narcotics, or by changing the neuron membrane. The external membrane of any cell is a lipid (wax or oil). "Floating" in the lipid are the proteins which give a cell its shape, and in neurons, the proteins which serve as ion channels, receptors and transporters. The long "tail" on THC indicates that it *can* dissolve in lipids and have an effect by changing how easily the proteins move around in the lipid. However, for the last 20 years we've known that there are specific receptors that respond specifically to the "cannabinoid" drugs. Fifteen years ago the first "endogenous" or naturally occurring cannabinoid-like chemicals were identified in the brain, and about 10 years ago we discovered what those chemicals do. We know that THC and the cannabinoids have the potential to affect *all* of the other neurotransmitters, because the natural chemicals can change how much neurotransmitter is released on a moment-by-moment basis.

So, the secret to *why* abused drugs have an effect, is that they look like the normal brain chemicals. The issue of *how* they have an effect depends on what the normal role of the neurotransmitter is: Norepinephrine is involved in attention => amphetamine is a stimulant; Dopamine is involved in risk/reward circuits => cocaine produces an extreme pleasurable "rush"; Serotonin is involved in sleep, dreaming and modulating sensory information => LSD causes hallucinations; GABA is the main inhibitor in the brain => ethanol relaxes and eventually depresses neuron activity; enkaphalin modulates pain = > heroin reduces pain to the point of producing euphoria. There are many more drugs that could be mentioned, but most fall into these main categories, and the common feature is interference with natural neurotransmitter function.

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Next up, two Weekend Special posts, then back to the Guide with "What's the Code" on Monday, May 2. Until next time, beware of imitation neurotransmitters - because they might just be a good drug gone bad.